This report describes a 38-year-old male homosexual with acquired immune deficiency syndrome (AIDS) and a history of Isospora belli infestation treated with trimethoprim-sulfamethoxazole. At autopsy, intracellular and extracellular I. belli organisms were identified in the mucosa and lamina propria of small and large intestine as well as in mesenteric and tracheobronchial lymph nodes, where an associated granulomatous reaction was also present. Until now, Isosporiasis has been observed as intracellular parasites restricted to the columnar cells of the intestinal mucosa in humans hosts. This is, to the authors' knowledge, the first time that this protozoa has been observed invading beyond the intestinal wall. This patient's autopsy also demonstrated intestinal ulcerations proven microscopically to be caused by cytomegalovirus (CMV). In patients with AIDS and CMV enterocolitis, the authors have observed an unusual frequency of extraintestinal disseminated disease by microorganisms heretofore typically restricted to the intestinal mucosa (i.e., bacteremias resulting from Shigella species). The authors propose that, in AIDS patients, the profound immunodeficient state, possibly in conjunction with CMV-induced intestinal mucosal ulcerations, promotes access of other intestinal microorganisms, including I. belli, into lymphatic and vascular spaces, culminating in lymphohematogenous dissemination of their intestinal infestations.